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Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle

机译:增加循环GMP的药物可放大衰竭的大鼠心室中5-HT4引起的正性肌力反应

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摘要

Activation of 5-HT4 receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT4-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT4-mediated inotropic response. However, CNP increased the 5-HT4-mediated inotropic response as well as the β1-adrenoceptor (β1-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by l-NAME and ODQ, respectively, attenuated the 5-HT4-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT4 response, Sin-1 inhibited whereas l-NAME and ODQ enhanced the β1-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT4-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β1-AR and 5-HT4 receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different Gs-coupled receptors.
机译:衰竭心室中5-HT4受体的激活会引起cAMP依赖性正性肌力反应,这主要受cGMP抑制性磷酸二酯酶(PDE)3的限制。但是,PDE4发挥了另外的作用,但受到PDE3抑制作用的掩盖。这项研究的目的是评估由颗粒和可溶性鸟苷基环化酶(GC)产生的cGMP对5-HT4介导的肌力反应的影响。 Wistar大鼠冠状动脉结扎引起广泛的心肌梗塞,术后6周出现心力衰竭。测量左心室准备中的收缩力。循环GMP通过EIA测量。在心室准备中,ANP或BNP对5-HT4介导的肌力反应无影响。但是,CNP增加了5-HT4介导的肌力反应以及β1-肾上腺素能受体(β1-AR)介导的反应,其程度与西洛沙酰胺对PDE3的抑制作用相似。西洛他酰胺预处理消除了CNP的作用。 l-NAME和ODQ分别抑制一氧化氮(NO)合酶和可溶性GC,减弱了5-HT4介导的变力反应,而NO供体Sin-1增加了该反应。在PDE3抑制过程中没有这种作用,提示cGMP依赖的PDE3抑制作用。但是,与对5-HT4反应的影响相反,Sin-1受到抑制,而l-NAME和ODQ增强了β1-AR介导的肌力反应。颗粒(NPR-B)和可溶性GC生成的cGMP可能通过抑制PDE3增强了衰竭心脏中5-HT4介导的肌力反应。 β1-AR和5-HT4受体信号转导受到衰竭心脏中可溶性GC产生的cGMP的相反调控。因此,来自不同来源的cGMP在功能上是分开的,从而对不同的Gs偶联受体进行了不同的调节。

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